Cost-effectiveness analysis of influenza vaccination with a high-dose vaccine versus an adjuvanted quadrivalent vaccine in older adults in Spain

This cost-effectiveness analysis demonstrates that vaccinating older adults in Spain with a high-dose quadrivalent influenza vaccine is a dominant strategy over an adjuvanted quadrivalent vaccine, as it reduces influenza cases, hospitalizations, and deaths while lowering overall costs from both societal and National Health Service perspectives.

The Gist

Imagine your body is a castle, and the winter flu is a relentless army of invaders trying to breach the walls. For older adults (those over 65), the castle walls are a bit weaker, and the guards (the immune system) are a bit slower to react. To help, we have two different types of "reinforcement troops" (vaccines) available in Spain: the High-Dose Vaccine (HD-QIV) and the Adjuvanted Vaccine (aQIV).

This study is like a massive simulation game where researchers asked: "If we send in the High-Dose troops instead of the Adjuvanted troops to protect the elderly, who wins, and does it save the kingdom money?"

Here is the breakdown of their findings in plain English:

1. The Two Contenders

• The Adjuvanted Vaccine (aQIV): Think of this as a standard shield with a special "booster" attached to it. It helps the immune system wake up a bit faster.
• The High-Dose Vaccine (HD-QIV): This is like a super-charged shield. It contains four times more of the active "soldier" (antigen) than a normal vaccine. It's designed specifically to punch harder against the flu in older bodies.

2. The Simulation (The Model)

Since we can't run a perfect head-to-head race between these two vaccines in real life right now (there's no direct study comparing them side-by-side), the researchers built a sophisticated digital crystal ball.

They fed this crystal ball with the best data available:

• How many people get sick?
• How many end up in the hospital?
• How much does it cost to treat them?
• How many lives are saved?

They ran the simulation for the entire population of older adults in Spain to see what happens if the country switches from the "Standard Shield" (Adjuvanted) to the "Super Shield" (High-Dose).

3. The Results: The "Super Shield" Wins Big

The simulation showed that switching to the High-Dose vaccine is a dominant strategy. In economics, "dominant" is a fancy way of saying: "It works better AND it costs less overall."

Here is what happened in the simulation over just one flu season:

• Fewer Sick People: The High-Dose vaccine stopped 54,000 extra cases of the flu.
• Fewer Hospital Visits: It prevented 1,500 emergency room visits and 27,000 hospitalizations. Imagine a hospital ward that suddenly has 27,000 fewer beds needed because people stayed home and healthy.
• Lives Saved: It prevented 1,203 deaths.
• Money Saved: Even though the High-Dose vaccine costs more to buy upfront, it saved the country nearly €100 million in total costs.

The Analogy: Think of it like buying a slightly more expensive, high-quality roof for your house. The roof costs more to install, but because it stops the rain so much better, you don't have to pay for thousands of dollars in water damage repairs, mold removal, and ruined furniture later. The High-Dose vaccine is the better roof; it stops the "rain" (flu) so effectively that you save money on the "repairs" (hospital bills).

4. Why Did It Save Money?

You might wonder, "If the vaccine is more expensive, how did they save money?"

The answer is simple: Hospital bills are huge.
Treating a flu patient in the hospital, especially an older adult with heart or lung issues, is incredibly expensive. It involves doctors, nurses, beds, and medicine.

• The High-Dose vaccine is so effective at keeping people out of the hospital that the money saved on those hospital bills completely covered the extra cost of buying the better vaccine.
• It also saved money by keeping people at work (or at home) instead of sick, which is good for the economy.

5. The Bottom Line

The researchers ran the numbers thousands of times (using different scenarios and assumptions) to make sure the result wasn't a fluke. Every time, the High-Dose vaccine came out on top.

The Verdict:
For older adults in Spain, switching to the High-Dose flu vaccine is the smartest move. It acts like a stronger shield that not only protects more people from getting sick and dying but also acts as a financial safety net for the healthcare system, saving millions of euros that would otherwise be spent on treating severe flu cases.

In short: Spend a little more now on the "Super Shield" to avoid paying a fortune later on "Emergency Repairs." It's a win for health, and a win for the wallet.

Technical Summary

1. Problem Statement

Seasonal influenza poses a significant public health and economic burden in Spain, particularly among adults aged ≥65 years. This demographic is highly susceptible to severe complications due to immunosenescence and comorbidities, accounting for the majority of influenza-related hospitalizations and excess deaths. While vaccination is the primary prevention strategy, vaccine effectiveness remains suboptimal in the elderly.

Two advanced vaccine strategies are currently available for this population:

• High-Dose Quadrivalent Vaccine (HD-QIV): Contains 4x the antigen (60 μg) of standard doses.
• Adjuvanted Quadrivalent Vaccine (aQIV): Contains standard antigen (15 μg) plus an MF59® adjuvant.

The Gap: There is a lack of head-to-head randomized controlled trials (RCTs) directly comparing HD-QIV and aQIV. Consequently, policymakers lack robust evidence to determine which strategy offers superior clinical outcomes and cost-effectiveness for the Spanish National Health Service (NHS) and society at large.

2. Methodology

The study employed a pharmacoeconomic decision-tree model to compare HD-QIV against aQIV for the Spanish population aged ≥65 years over a single influenza season (6-month horizon), with health outcomes (Life Years and QALYs) projected over a lifetime.

Model Structure and Inputs

• Perspective: Primary analysis from a societal perspective (including direct medical costs, healthcare resource use, and indirect costs like productivity loss). A secondary analysis was conducted from a healthcare (NHS) perspective.
• Population: Stratified into two age groups: 65–74 years and ≥75 years.
• Vaccine Efficacy (VE) Estimation:
  • Since no direct comparison exists, the model used indirect comparison via a common comparator: Standard-Dose Quadrivalent Vaccine (SD-QIV).
  • HD-QIV: Relative Vaccine Effectiveness (rVE) was derived from a meta-analysis of RCTs (Lee et al., 2023) and immunobridging data, assuming an absolute efficacy of 62.1% against influenza cases.
  • aQIV: Due to a lack of high-quality evidence showing superiority over SD-QIV, its absolute efficacy was conservatively assumed to be equal to SD-QIV (50% against cases).
  • Hospitalizations: rVE against cardiorespiratory hospitalizations was derived from meta-analyses (Lee et al., 2023; Skaarup et al., 2024) for HD-QIV. For aQIV, a cluster-randomized trial (McConeghy et al., 2021) was used as the highest available evidence, though results were noted as statistically non-significant for respiratory outcomes.
• Outcomes Modeled: Influenza cases, GP/ED visits, hospitalizations (Pneumonia/Influenza, Respiratory, Cardiorespiratory, All-cause), and mortality.
• Costs: Included vaccine acquisition, administration, hospitalization (with/without severe outcomes), GP/ED visits, and indirect costs (productivity loss via friction cost method). Costs were updated to 2023 Euros.
• Sensitivity Analysis:
  • Deterministic (DSA): One-way sensitivity analysis varying parameters by ±20% or using 95% CIs.
  • Probabilistic (PSA): 1,000 Monte Carlo simulations.
  • Thresholds: Willingness-to-pay (WTP) thresholds of €25,000 and €34,000 per QALY were applied.

3. Key Contributions

• Evidence Synthesis: The study addresses the critical evidence gap regarding HD-QIV vs. aQIV by utilizing the highest available level of evidence (meta-analyses of RCTs and observational studies) to construct an indirect comparison model.
• Methodological Rigor: It explicitly critiques previous studies (e.g., Ruiz-Aragón et al., 2022) for relying on non-peer-reviewed meta-analyses or assuming comparable performance between vaccines without robust data. This study prioritizes transparent, publicly available data sources.
• Broad Outcome Definition: The base case utilizes a cardiorespiratory hospitalization definition rather than just pneumonia/influenza, acknowledging that influenza often destabilizes chronic cardiovascular conditions, thereby capturing a more realistic burden of disease.
• Comprehensive Costing: The inclusion of indirect costs (productivity loss) provides a holistic view of the economic impact on Spanish society, not just the healthcare system.

4. Key Results

The analysis demonstrated that HD-QIV is a dominant strategy over aQIV, meaning it is both more effective and less costly.

• Clinical Outcomes (Societal Perspective):
  • Cases Prevented: 54,039 influenza cases.
  • Healthcare Utilization: 7,733 fewer GP consultations, 1,585 fewer ED visits, and 27,398 fewer cardiorespiratory hospitalizations.
  • Mortality: 1,203 deaths prevented.
  • Health Gains: 14,316 Life Years (LYs) and 12,440 Quality-Adjusted Life Years (QALYs) gained over a lifetime.
• Economic Outcomes:
  • Total Cost Savings: Despite the higher acquisition cost of HD-QIV, the reduction in downstream healthcare costs and productivity losses resulted in a net saving of €98.2 million for society.
  • NHS Perspective: From the healthcare perspective alone, HD-QIV saved €77.4 million while gaining 12,440 QALYs.
• Sensitivity Analysis:
  • The dominance of HD-QIV was robust across all scenarios.
  • In the Probabilistic Sensitivity Analysis (PSA), HD-QIV remained the dominant strategy in 98.9% of iterations.
  • The probability of HD-QIV being cost-effective was 100% at both €25,000 and €34,000 per QALY thresholds.

5. Significance and Conclusion

This study provides robust evidence that for the Spanish population aged ≥65, HD-QIV should be the preferred vaccination strategy over aQIV.

• Policy Implication: The findings support a shift in vaccination policy to prioritize HD-QIV, not only to improve public health outcomes (reducing mortality and severe morbidity) but also to optimize resource allocation. HD-QIV generates substantial cost savings for both the NHS and society, making it a highly attractive option in a context of budgetary constraints.
• Clinical Impact: By preventing nearly 28,000 cardiorespiratory hospitalizations and freeing up ~236,000 bed-days in a single season, HD-QIV offers a critical tool for alleviating pressure on Spanish healthcare systems during winter peaks.
• Limitations Acknowledged: The authors note the reliance on indirect comparisons due to the absence of head-to-head RCTs and the use of a static model rather than a dynamic transmission model. However, they argue that the use of the highest-quality available evidence and conservative assumptions strengthens the validity of the conclusion that HD-QIV is the superior strategy.

In summary, the paper concludes that vaccinating older adults in Spain with HD-QIV instead of aQIV is a dominant strategy, effectively reducing disease burden, mortality, and total costs.